Stress-related functional bowel disease, including irritable bowel syndrome, irritable colon syndrome, spastic colon and irritable colon, is a common, often incapacitating gastrointestinal disorder in mammals. In humans, it is the most common chronic gastrointestinal disorder in adults and ranks equally with the common cold as the leading cause of illness-related absenteeism from the work place. Diagnosis of this disease is based on a vague symptomatology that includes abdominal pain and diarrhea, constipation, or alternating episodes of both, and treatment of the disorder is largely disappointing relative to relief and prevention of the prevailing symptoms. The etiology of intestinal dysfunction due to stress, or exacerbated by stress, is completely unknown, however, available evidence suggests that the disorder results from motility changes in the small intestine and colon brought on or exacerbated by stress.
Stress is a complex reaction that is characterized by activation of both endocrine and autonomic systems. The hypothalamic-pituitary-adrenal axis is the endocrine axis most central to the stress response, and the sympathetic nervous system, including the adrenal medulla, is the branch of the autonomic nervous system that is thought to be activated by acute stress. Corticotropin-releasing factor (CRF), a peptide comprising 41 amino acid residues and first characterized from ovine hypothalamic extracts (Vale et al., 1981, Science Wash. DC 213:1394-1397), is capable of activating both major systems. In addition to its role as the principal regulator of pituitary adrenocorticotropic hormone (ACTH) release (Rivier et al., 1982, Endocrinology 110:272-278), CRF has been shown to have a number of effects within the central nervous system: CRF elicits behavioral activation in rats (Sutton et al., 1982, Nature Lond. 297:331-333); stimulates the sympathoadrenomedullary pathway (Brown et al., 1982, Endocrinology 111:928-931); increases heart rate and blood pressure (Fisher et al., 1982, Endocrinology 10:2222-2224); and suppresses food consumption (Levine et al., 1983, Neuropharmacology 22:337-339) and sexual activity (Sirinathsinghji et al., 1983, Nature Lond. 305:230-235). CRF has also been shown to affect gastrointestinal function. Administered into the brain, CRF suppresses gastric acid secretion (Tache et al., 1983, Science Wash. DC 222:935-937), inhibits gastric emptying (Hagiwara et al. Gastroenterology 90:1447) and suppresses gastric and small intestinal motility (Bueno and Fioramonti, 1986, Peptides 7:73-77; Konturek et al., 1985, Life Sci. 37:1231-1240). The effects of CRF on small and large intestinal transit have not been evaluated. Because of its wide distribution within the brain and its multiple actions, which are generally associated with stress, CRF has been proposed as a "master transmitter", capable of eliciting coordinated endocrine and autonomic events characteristic of the stress response.
In accordance with the present invention, the inventors determine the role CRF plays in mediating the effects of stress on the gastrointestinal tract, by studying the actions of exogenous CRF on gastrointestinal transit using an animal model developed to study the effects of stress on intestinal motor function. As disclosed herein, the surprising discovery is made that an antagonist to CRF blocks the effects of stress on intestinal function. Accordingly, the present invention fulfils a long felt need to develop an effective treatment for stress-related functional bowel disease by the administration of effective anatagonists of CRF.